Non-obese diabetic (NOD) mice spontaneously develop diabetes which resembles human type I insulin-dependent diabetes mellitus (IDDM). The objectives of this grant application (1) are to use a novel adoptive transfer model to attempt to identify various stages of inflammation leading to beta cell destruction (2), to identify which cells are involved in insulitis versus beta cell destruction (3), to characterize what beta cell-specific antigens are recognized at various stages of inflammation, and (4) whether a restricted subset to T cells is involved in the early pathophysiologic events leading to infiltrative insulitis and resultant beta cell destruction in NOD disease. The NOD/Scid/Scid (NOD/Scid) mouse has recently been developed and offers a novel adoptive transfer model for studying the evolution of diabetogenesis in NOD mice. Unlike adoptive transfer models described to date, adoptive transfer of lymphocytes from NOD mice into NOD/Scid recipients allows an analysis of the pathophysiology of events form insulitis through beta cell destruction. Adoptive transfer of islet-infiltrating lymphocytes allows an analysis of subset requirements, T cell receptor expression, and beta cell antigen recognized by those cells aims of this grant application intend to allow an analysis of the pathophysiology of inflammatory insulitis with resultant hyperglycemia as it develops in the NOD/Scid adoptive recipient of either peripheral lymphocytes or islet-infiltrating lymphocytes from NOD mice. Preliminary studies outlined in the body of this grant application indicate the feasibility of these studies and suggest the appropriateness of the NOD/Scid mouse as a model of adoptive transfer. Identification of T cell subsets involved in various stages of inflammatory insulitis leading to beta cell destruction, as well as identification of antigens recognized by such T cell subsets, should provide an exciting approach to the development of specific immunotherapy for the prevention of diabetes in the NOD mouse model. Such studies may well have clinical relevance to understanding the pathophysiology and developing strategies for therapy of human IDDM.